CHD4

chromodomain helicase DNA binding protein 4, the group of NuRD complex subunits|Small nucleolar RNA protein coding host genes|PHD finger proteins

Basic information

Region (hg38): 12:6570081-6614524

Links

ENSG00000111642 ∙ NCBI:1108 ∙ OMIM:603277 ∙ HGNC:1919 ∙ Uniprot:Q14839 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• Sifrim-Hitz-Weiss syndrome (Moderate), mode of inheritance: AD
• Sifrim-Hitz-Weiss syndrome (Strong), mode of inheritance: AD
• syndromic intellectual disability (Definitive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Sifrim-Hitz-Weiss syndrome	AD	Audiologic/Otolaryngologic; Cardiovascular	Among other features, the condition can include hearing loss, and early recognition and treatment of hearing impairment may improve outcomes, including speech and language development; The condition can involve congenital cardiac anomalies, and awareness may allow early management	Audiologic/Otolaryngologic; Cardiovascular; Craniofacial; Gastrointestinal; Genitourinary; Musculoskeletal; Neurologic	21743468; 27479907; 27616479

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the CHD4 gene.

• not provided (284 variants)
• Sifrim-Hitz-Weiss syndrome (64 variants)
• Inborn genetic diseases (35 variants)
• not specified (11 variants)
• CHD4-related condition (10 variants)
• Intellectual disability (2 variants)
• See cases (2 variants)
• Global developmental delay (1 variants)
• Neonatal encephalopathy (1 variants)
• CHD4-Related Disorder (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the CHD4 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			3	50	30	83
missense	5	31	146	12	7	201
nonsense			5			5
start loss						0
frameshift		2	7			9
inframe indel			10	1		11
splice donor/acceptor (+/-2bp)		1	3			4
splice region			7	18	6	31
non coding			5	22	7	34
Total	5	34	179	85	44

Highest pathogenic variant AF is 0.00000658

Variants in CHD4

This is a list of pathogenic ClinVar variants found in the CHD4 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
12-6570700-A-G			Likely benign (Jul 19, 2022)
12-6570710-G-A			Benign (Jan 26, 2024)
12-6570874-G-A			Uncertain significance (May 02, 2022)
12-6570879-G-A			Uncertain significance (Oct 01, 2023)
12-6570887-G-A			Likely benign (Jan 17, 2024)
12-6570887-G-T			Likely benign (May 10, 2018)
12-6570891-G-A			Likely benign (Oct 13, 2023)
12-6570895-G-A		Sifrim-Hitz-Weiss syndrome	Uncertain significance (Mar 26, 2024)
12-6570895-G-C		CHD4-related disorder	Uncertain significance (Mar 27, 2023)
12-6570896-G-A			Likely benign (Sep 18, 2022)
12-6570921-C-A		Sifrim-Hitz-Weiss syndrome	Uncertain significance (May 22, 2020)
12-6570921-C-T			Uncertain significance (Sep 01, 2023)
12-6570952-G-A		Moyamoya angiopathy with developmental delay	Likely pathogenic (-)
12-6570964-C-T			Likely benign (Jun 13, 2022)
12-6570970-T-C		Inborn genetic diseases	Uncertain significance (Feb 28, 2024)
12-6571041-G-A		CHD4-related disorder	Likely benign (Aug 01, 2022)
12-6571050-G-A			Likely benign (Jan 22, 2024)
12-6573066-C-T			Likely benign (Jan 15, 2022)
12-6573078-G-A			Uncertain significance (Nov 13, 2023)
12-6573088-G-A			Uncertain significance (Dec 23, 2021)
12-6573102-G-A		Sifrim-Hitz-Weiss syndrome	Benign/Likely benign (Jun 03, 2023)
12-6573124-G-C		Sifrim-Hitz-Weiss syndrome	Uncertain significance (Sep 28, 2022)
12-6573128-G-A			Benign (Nov 15, 2022)
12-6573159-C-G		Sifrim-Hitz-Weiss syndrome	Uncertain significance (Sep 05, 2019)
12-6573177-G-C			Benign (Aug 28, 2021)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
CHD4	protein_coding	protein_coding	ENST00000357008	39	37394

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.00	6.36e-11	125724	0	24	125748	0.0000954

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	6.34	504	1.09e+3	0.461	0.0000644	12640
Missense in Polyphen		120	381.01	0.31495		4232
Synonymous	-0.523	400	387	1.03	0.0000205	3564
Loss of Function	8.76	10	108	0.0922	0.00000659	1221

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000363	0.000362
Ashkenazi Jewish	0.00	0.00
East Asian	0.000109	0.000109
Finnish	0.00	0.00
European (Non-Finnish)	0.0000795	0.0000791
Middle Eastern	0.000109	0.000109
South Asian	0.000166	0.000163
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Component of the histone deacetylase NuRD complex which participates in the remodeling of chromatin by deacetylating histones. {ECO:0000269|PubMed:17626165, ECO:0000269|PubMed:9804427}.
• Disease: DISEASE: Sifrim-Hitz-Weiss syndrome (SIHIWES) [MIM:617159]: An autosomal dominant syndrome characterized by mental retardation, variable congenital defects affecting cardiac, skeletal, and urogenital systems. Short stature, macrocephaly, hearing impairment, and facial dysmorphism are present in some patients. {ECO:0000269|PubMed:27479907, ECO:0000269|PubMed:27616479}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Viral carcinogenesis - Homo sapiens (human);Human papillomavirus infection - Homo sapiens (human);ERCC6 (CSB) and EHMT2 (G9a) positively regulate rRNA expression;Positive epigenetic regulation of rRNA expression;Signal Transduction;Epigenetic regulation of gene expression;Gene expression (Transcription);Generic Transcription Pathway;HDACs deacetylate histones;RNA Polymerase I Promoter Clearance;RNA Polymerase II Transcription;Chromatin modifying enzymes;RNA Polymerase I Transcription;RNA Polymerase I Transcription Initiation;Regulation of PTEN gene transcription;PTEN Regulation;PIP3 activates AKT signaling;Chromatin organization;Regulation of TP53 Activity through Acetylation;Regulation of TP53 Activity;Transcriptional Regulation by TP53;Intracellular signaling by second messengers;Signaling events mediated by HDAC Class I (Consensus)

Recessive Scores

• pRec: 0.318

Intolerance Scores

• loftool: 0.0568
• rvis_EVS: -1.64
• rvis_percentile_EVS: 2.82

Haploinsufficiency Scores

• pHI: 0.802
• hipred: Y
• hipred_score: 0.704
• ghis: 0.610

Essentials

• essential_gene_CRISPR: E
• essential_gene_CRISPR2: E
• gene_indispensability_pred: E
• gene_indispensability_score: 0.979

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium

Mouse Genome Informatics

• Gene name: Chd4
• Phenotype: immune system phenotype; embryo phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); hematopoietic system phenotype; growth/size/body region phenotype; endocrine/exocrine gland phenotype; cellular phenotype

Gene ontology

• Biological process: regulation of transcription by RNA polymerase II;histone deacetylation;DNA duplex unwinding;ATP-dependent chromatin remodeling
• Cellular component: nuclear chromatin;nucleus;nucleoplasm;cytoplasm;centrosome;membrane;NuRD complex;protein-containing complex
• Molecular function: RNA polymerase II proximal promoter sequence-specific DNA binding;RNA polymerase II distal enhancer sequence-specific DNA binding;RNA polymerase II repressing transcription factor binding;DNA binding;ATP-dependent DNA helicase activity;histone deacetylase activity;protein binding;ATP binding;zinc ion binding;nucleosomal DNA binding;histone deacetylase binding